Updated results from the ELARA trial of tisa-cel in R/R follicular lymphoma

The Lymphoma Hub has previously reported on the interim analysis of the ELARA trial (NCT03568461) for adult patients with relapsed/refractory (R/R) follicular lymphoma (FL). This analysis was presented during the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition by the Nathan Fowler, a Lymphoma Hub Executive Steering Committee member. Recently, at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting, the primary analysis of the phase II ELARA trial was presented by Stephen Schuster. Here we provide a summary of the updated findings.

Study design

ELARA is a single-arm, multicenter, phase II study evaluating the efficacy and safety of tisagenlecleucel (tisa-cel), a chimeric antigen receptor (CAR) T-cell therapy, in patients with R/R FL; further details can be found here.

The primary endpoint was complete response rate assessed by an Independent Review Committee based on the 2014 Lugano classification. The secondary endpoints included overall response rate, duration of response, progression-free survival (PFS), overall survival, and cellular kinetics.

Baseline characteristics

A total of 97 patients were enrolled, with a median age of 57 years (range, 29–73 years). The eligible patients were heavily pretreated, with a median of four prior therapies (range, 2–13). Approximately 76% of patients were refractory to ≥2 regimens (Table 1). The median infused dose of tisa-cel was 2.06 × 10⁸ CAR+ viable T cells.

Table 1. Baseline characteristics*

Auto-HSCT, autologous hematopoietic stem cell transplantation; ECOG PS, European Cooperative Oncology Group performance status; FLIPI, follicular lymphoma international prognostic factor index; mAb, monoclonal antibody; PI3K, phosphoinositide 3-kinase. *Adapted from Schuster et al.1
Characteristic, %	Total (N = 97)
ECOG PS
0	58
1	38
2	4
Prior therapies
≥5	28
Auto-HSCT	36
Anti-CD20 mAb and alkylating agents	65
PI3K inhibitors	21
Lenalidomide and rituximab	17
Stage III-IV disease	85
FLIPI ≥3	60
Refractory to last line of therapy	78
Refractory to ≥2 regimens	76

Results

Efficacy

• A total of 94 patients were evaluable for efficacy. Independent Review Committee-assessed complete response rate and overall response rate were 66% and 86%, respectively (Table 2), and these were consistent across key high-risk subgroups.
• The proportion of patients maintaining a response ≥6 months was 79% (95% confidence interval, 66–87).
• Among patients with a partial response, 39% converted to a complete response.
• Median PFS, overall survival, and duration of response were not attained at the median follow-up of 10.9 months (range, 4.3–19.7 months).
• The 6-month PFS was 76% (95% confidence interval, 65–84).

Table 2. IRC-assessed response rate*

CI, confidence interval; CR, complete response; IRC, Independent Review Committee; ORR, overall response rate; PR, partial response. *Adapted from Schuster et al.1 †p < 0.0001; indicates statistical significance (1-sided) at the 0.0025 level so that the null hypothesis CRR≤0.15 is rejected.
Response rate, %	Total (n = 94)
CR	66† (95% CI, 56–75)
PR	20
ORR (CR+PR)	86 (95% CI, 78–92)

Safety

• Almost all patients (99%) experienced an adverse event (AE) of any grade, and 77% of all AEs were suspected to be treatment-related. Three deaths occurred due to disease progression.
• Grade 3/4 AEs were observed in 76% of patients, and the most common Grade ≥3 AEs of special interest within 8 weeks post-infusion were neutropenia (28%) and anemia (13%) (Table 3).
• All neurological events and cases of cytokine release syndrome (CRS) were managed appropriately, including with tocilizumab (34%) and corticosteroids (6%).
• Median onset of neurological events was 8.5 days (range, 4–190 days) and median onset of CRS was 4 days (range, 1–14 days).
• CRS events were all low grade and 75% occurred in patients with bulky disease. Only one case of immune effector cell-associated neurotoxicity syndrome occurred in the first 8 weeks.

Table 3. AEs of special interest observed for all patients*

AE, adverse event; CRS, cytokine release syndrome. *Adapted from Schuster et al.1 †Median duration of Grade 3 or 4 neutropenia was 52 days. ‡Prolonged depletion, defined as lasting ≥28 days.
AE of special interest (within 8 weeks of infusion), %	All grades	Grade ≥3
CRS	49	0
Neurological adverse reactions	9	1
Infections	19	5
Hematologic disorders including cytopenia
Neutropenia†	31	28
Anemia	25	13
Thrombocytopenia	17	9
Tumor lysis syndrome	1	1
Prolonged depletion‡ of B cells and/or agammaglobulinemia (IgG <4 g/L)	10	0

Cellular kinetics

• Similar levels of geometric mean estimate for expansion and area under the curve from Day 0–28 were seen between responders (both complete response and partial response) and non-responders (stable or progressive disease).
• Maximum transgene levels were achieved by a median of 10 days vs 13 days in responders and non-responders, respectively.
• Transgene persistence was detected for up to 370 days vs 187 days in responders and non-responders, respectively.

Conclusion

The study demonstrated that tisa-cel had high rates of durable responses and these responses were effective and comparable across high-risk subgroups. No cases of high-grade CRS, no treatment related mortality, and low levels of neurotoxicity were consistent with the established favorable safety profile of tisa-cel. The positive findings from the study warrant further investigation of tisa-cel as a treatment for adult patients with R/R FL following ≥2 lines of therapy.